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Follicle Stimulating Hormone (FSH) to Improve Testicular Development in Men With Hypogonadism

Primary Purpose

Hypogonadism, Kallmann Syndrome

Status
Terminated
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Testicular biopsy
gonadotropin releasing hormone (GnRH)
follicle stimulating hormone (FSH)
Sponsored by
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Hypogonadism focused on measuring Male reproduction hormones, Hypogonadotropic hypogonadism, FSH, LH, GnRH

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)MaleDoes not accept healthy volunteers

Inclusion Criteria no history of spontaneous puberty clinical hypogonadism infantile testes (< 3 ml) no reproductive hormone therapy except testosterone Complete absence of normal LH pulses during 12-hour baseline frequent blood sampling and serum testosterone < 100 ng/dl Normal testing of the anterior pituitary gland Negative MRI of the hypothalamic-pituitary area Exclusion Criteria Prior therapy with gonadotropins (FSH, hCG, or GnRH)

Sites / Locations

  • Massachusetts General Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Group 1 (FSH)

Group 2 (GnRH)

Arm Description

Patients in Group 1 will receive subcutaneous follicle stimulating hormone (FSH) injections daily, titrated to achieve a FSH level of 4-8 IU/L, for 4 months. Patients will then receive gonadotropin releasing hormone (GnRH) therapy for 18 months. GnRH will be administered via a portable infusion pump at 2-hour intervals to stimulate endogenous LH secretion.

Patients in Group 2 will receive gonadotropin releasing hormone (GnRH) therapy for 18 months. GnRH will be administered via a portable infusion pump at 2-hour intervals to stimulate endogenous LH secretion. Patients in Group 2 will not receive prior FSH administration.

Outcomes

Primary Outcome Measures

LH
Average Luteinizing Hormone levels after treatment.
FSH
Average Follicle Stimulating Hormone levels after treatment.
Testosterone
Average Testosterone levels after treatment.
Inhibin B
Average Inhibin B Levels after treatment.
Testicular Size (Volume)
Average testicular volume after treatment.
Sperm Count
Average sperm count after treatment.

Secondary Outcome Measures

Fertility
Participants actively seeking to conceive.

Full Information

First Posted
July 16, 2003
Last Updated
July 5, 2017
Sponsor
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
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1. Study Identification

Unique Protocol Identification Number
NCT00064987
Brief Title
Follicle Stimulating Hormone (FSH) to Improve Testicular Development in Men With Hypogonadism
Official Title
Role of FSH in Human Gonadal Development
Study Type
Interventional

2. Study Status

Record Verification Date
July 2017
Overall Recruitment Status
Terminated
Why Stopped
Recruitment was at a standstill. We are currently preparing our results for publication.
Study Start Date
April 2001 (undefined)
Primary Completion Date
October 2012 (Actual)
Study Completion Date
October 2012 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Men with idiopathic hypogonadotropic hypogonadism (IHH, Kallmann Syndrome) may have small testicular size, low testosterone levels, no history of puberty, and infertility. These men lack a hormone called gonadotropin releasing hormone (GnRH) that stimulates the development and maturation of the testes. This study will investigate the impact of hormonal treatments on men with IHH. The goal of hormonal therapy is to maximize the potential fertility in these individuals.
Detailed Description
Though steroid output of the testes is minimal during childhood, important changes take place that impact spermatogenic potential. Specifically, the number of Sertoli cells increases until testosterone secretion rises during puberty. In animal models, the proliferation of Sertoli cells appears to be regulated by follicle stimulating hormone (FSH) even though FSH levels in childhood are relatively low. At puberty, the number of Sertoli cells becomes fixed; however, the existing cell population then undergoes functional maturation. This switch from proliferation to maturation of Sertoli cells appears to result from rising levels of intratesticular testosterone. FSH deficiency during testicular development results in decreased numbers of Sertoli cells, even if physiologic hormonal replacement therapy is introduced in adolescence or adulthood. The number of mature Sertoli cells appears to correlate with testicular size, sperm count, and future fertility. An improved understanding of the specific roles of FSH, luteinizing hormone (LH), and testosterone in testicular development may have direct clinical applications in the treatment of male infertility. This study will define the role of FSH in stimulating Sertoli cell proliferation in the human male. Patients in this study will be randomized to receive either FSH and GnRH (Group 1) or GnRH alone (Group 2). Patients in Group 1 will receive subcutaneous FSH injections daily, titrated to achieve a FSH level of 4-8 IU/L, for 4 months. Patients will then receive GnRH therapy for 18 months. GnRH will be administered via a portable infusion pump at 2-hour intervals to stimulate endogenous LH secretion. Patients in Group 2 will receive the same regimen of exogenous GnRH for 18 months without prior FSH administration. All patients will undergo an initial assessment that includes an overnight 12-hour frequent blood sampling study, testicular ultrasound, and testicular biopsy. Patients will be followed through monthly study visits with blood tests and seminal fluid analysis. Patients will also have serial testicular ultrasounds to measure testicular growth. Patients in Group 1 will also have a second frequent blood sampling to measure LH, FSH, and testosterone and to confirm the absence of LH pulses.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hypogonadism, Kallmann Syndrome
Keywords
Male reproduction hormones, Hypogonadotropic hypogonadism, FSH, LH, GnRH

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
19 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Group 1 (FSH)
Arm Type
Experimental
Arm Description
Patients in Group 1 will receive subcutaneous follicle stimulating hormone (FSH) injections daily, titrated to achieve a FSH level of 4-8 IU/L, for 4 months. Patients will then receive gonadotropin releasing hormone (GnRH) therapy for 18 months. GnRH will be administered via a portable infusion pump at 2-hour intervals to stimulate endogenous LH secretion.
Arm Title
Group 2 (GnRH)
Arm Type
Active Comparator
Arm Description
Patients in Group 2 will receive gonadotropin releasing hormone (GnRH) therapy for 18 months. GnRH will be administered via a portable infusion pump at 2-hour intervals to stimulate endogenous LH secretion. Patients in Group 2 will not receive prior FSH administration.
Intervention Type
Procedure
Intervention Name(s)
Testicular biopsy
Intervention Description
Outpatient surgical procedure.
Intervention Type
Drug
Intervention Name(s)
gonadotropin releasing hormone (GnRH)
Intervention Description
Pulsatile GnRH (25 ng/kg per bolus every two hours via microinfusion pump titrated to reach normal serum testosterone levels)
Intervention Type
Drug
Intervention Name(s)
follicle stimulating hormone (FSH)
Other Intervention Name(s)
Gonal-F
Intervention Description
75 IU subcutaneous injection daily for four months.
Primary Outcome Measure Information:
Title
LH
Description
Average Luteinizing Hormone levels after treatment.
Time Frame
month 4 of GnRH treatment
Title
FSH
Description
Average Follicle Stimulating Hormone levels after treatment.
Time Frame
month 4 of GnRH treatment
Title
Testosterone
Description
Average Testosterone levels after treatment.
Time Frame
month 4 of GnRH treatment
Title
Inhibin B
Description
Average Inhibin B Levels after treatment.
Time Frame
month 4 of GnRH treatment
Title
Testicular Size (Volume)
Description
Average testicular volume after treatment.
Time Frame
at baseline and month 4 of GnRH treatment
Title
Sperm Count
Description
Average sperm count after treatment.
Time Frame
month 4 of GnRH treatment
Secondary Outcome Measure Information:
Title
Fertility
Description
Participants actively seeking to conceive.
Time Frame
24 months

10. Eligibility

Sex
Male
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria no history of spontaneous puberty clinical hypogonadism infantile testes (< 3 ml) no reproductive hormone therapy except testosterone Complete absence of normal LH pulses during 12-hour baseline frequent blood sampling and serum testosterone < 100 ng/dl Normal testing of the anterior pituitary gland Negative MRI of the hypothalamic-pituitary area Exclusion Criteria Prior therapy with gonadotropins (FSH, hCG, or GnRH)
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
William F Crowley, Jr., MD
Organizational Affiliation
Massachusetts General Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
Massachusetts General Hospital
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02114
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
12213860
Citation
Pitteloud N, Hayes FJ, Dwyer A, Boepple PA, Lee H, Crowley WF Jr. Predictors of outcome of long-term GnRH therapy in men with idiopathic hypogonadotropic hypogonadism. J Clin Endocrinol Metab. 2002 Sep;87(9):4128-36. doi: 10.1210/jc.2002-020518.
Results Reference
background
PubMed Identifier
11788640
Citation
Pitteloud N, Hayes FJ, Boepple PA, DeCruz S, Seminara SB, MacLaughlin DT, Crowley WF Jr. The role of prior pubertal development, biochemical markers of testicular maturation, and genetics in elucidating the phenotypic heterogeneity of idiopathic hypogonadotropic hypogonadism. J Clin Endocrinol Metab. 2002 Jan;87(1):152-60. doi: 10.1210/jcem.87.1.8131.
Results Reference
background
PubMed Identifier
11701733
Citation
Hayes FJ, Pitteloud N, DeCruz S, Crowley WF Jr, Boepple PA. Importance of inhibin B in the regulation of FSH secretion in the human male. J Clin Endocrinol Metab. 2001 Nov;86(11):5541-6. doi: 10.1210/jcem.86.11.8031.
Results Reference
background
PubMed Identifier
16396935
Citation
Kumar PA, Pitteloud N, Andrews PA, Dwyer A, Hayes F, Crowley WF Jr, Dym M. Testis morphology in patients with idiopathic hypogonadotropic hypogonadism. Hum Reprod. 2006 Apr;21(4):1033-40. doi: 10.1093/humrep/dei444. Epub 2006 Jan 5.
Results Reference
background
PubMed Identifier
24037890
Citation
Dwyer AA, Sykiotis GP, Hayes FJ, Boepple PA, Lee H, Loughlin KR, Dym M, Sluss PM, Crowley WF Jr, Pitteloud N. Trial of recombinant follicle-stimulating hormone pretreatment for GnRH-induced fertility in patients with congenital hypogonadotropic hypogonadism. J Clin Endocrinol Metab. 2013 Nov;98(11):E1790-5. doi: 10.1210/jc.2013-2518. Epub 2013 Sep 13.
Results Reference
derived

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Follicle Stimulating Hormone (FSH) to Improve Testicular Development in Men With Hypogonadism

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